Our long-term objective is to identify safe and effective natural agents to prevent menopausal symptoms and osteoporosis. Currently, there are 36 million postmenopausal women in the USA, and this number is projected to soar to 50 million by the year 2020. Menopause is characterized by severe estrogen deficiency, which leads to hot flushes, vaginal dryness, mood swings and osteoporosis. Although these conditions have been effectively treated with hormone replacement therapy (HILT) for the past 50 years, recent clinical trials have found that HRT is associated with increased risk of breast cancer, cardiovascular disease and dementia. The failure of HRT to live up to expectations has left the rapidly expanding menopausal population without a good alternative that prevents both hot flushes and osteoporosis. Thus, there is a tremendous need to discover more selective and safer estrogens. Many women seek alternatives to HRT, particularly estrogens derived from plants, known as phytoestrogens. Interest in phytoestrogens has been fueled by observational studies showing a lower incidence of menopausal symptoms, osteoporosis, cardiovascular disease and breast cancer in Asian women who consume soy and herbal products. Unfortunately, little scientific data exists to show that they are effective at preventing menopausal symptoms and osteoporosis. Based on our studies showing that estrogen receptor (ER) alpha mediates breast cancer cell proliferation and ERBeta inhibits proliferation and breast tumor formation in mouse xenografts, we are using molecular biology techniques to identify herbs that exhibit selective estrogenic activity for ERBbeta. We hypothesize that ERBeta-selective estrogens will be safer than estrogens found in current HRT regimens that interact non-selectively with ERalpha and ERBeta, and will be effective at reducing hot flushes and osteoporosis. To discover ERbeta-selective herbs, we screened 67 Chinese herbs using transient transfection assays with luciferase reporters in the presence of ERalpha or ERBeta Seven herbs selectively regulated transcription with ERli Some of these herbs also recruited the coregulator, GRIP1 to ERBeta, and were very weak at causing the proliferation of MCF-7 breast cancer cells. The goals of this proposal are to: (1) employ molecular biology techniques to determine how herbs are ER-selective and if the herbs retain ER-selectivity in vivo. (2) identify active compounds in herbs responsible for ER-selectivity. (3) identify which class of ER-selective herbs are most effective at reducing the frequency and severity of hot flushes. Identifying ER-selective herbs could lead to the discovery of novel agents that retain the beneficial effects on bone and menopausal symptoms, but lack the cancer promoting properties of estrogens in current HRT on the breast and endometrium.